R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018

R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018
Renal Cell Carcinoma R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018

Epidemiology Kidney & renal pelvis cancer
3.8% new cancer cases/year in US Median age: dx = 64 death = 71 70% found incidentally 30-40% p/w or will develop mets 2018 estimates: 65,340 diagnosed with RCC 14,970 will die of RCC Incidence rising 0.7% / yr Death rate falling 0.9% / yr since 2005…

Epidemiology continued
Risk factors: Smoking Obesity HTN Hereditary (approx. 2% of cases. VHL most common) 5 yr survival (SEER) 92.6% localized 11.7% advanced (7% in pre-TKI era)

Renal mass ~90% of renal tumors are RCC Benign renal tumors
Angiomyolipoma, cyst, leiomyoma Other malignant renal tumors Renal sarcoma or peri-renal sarcoma Lymphoma Wilms tumor Urothelial CA

Histology 80% clear cell histology Papillary Chromophobe
Collecting duct / medullary assoc w/ SC trait Oncocytoma (benign) Sarcomatoid features – worse prognosis Metastases lung, LN, bone, liver, adrenals, brain

Medscape.com

PFS: Oncocytoma > Chromophobe > Type I Papillary > Type II Papillary > Clear Cell
Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Molecular / cytogenetic abnormalities in RCC
Histology Cytogenetics Molecular Abnormality Familial Syndrome Clear Cell Loss of heterozygosity 3p / mutation of 3p25 (VHL) VHL inactivating mutation or hypermethyl PBRM1 SETD2 BAP1 TORC1 VHL Disease Papillary +7, +17, -Y, complex cytogenetics C-MET mutation (7q31) Fumarate hydratase (1q42) inactivation Hereditary Papillary RCC Hereditary leiomyomatosis RCC Chromophobe -1, -2, -6, -10, -13, -17, -17, -21 FLCN mutation TP53 mutations ND5 mutations Birt-Hogg Dube Syndrome (FLCN mutation) Oncocytoma -1, -Y, CCND1, loss of 14q Birt-Hogg Dube Familial Oncocytoma

Role of VHL Tumor suppressor gene
Encodes for a protein  destruction of HIF-1α HIF encodes for VEGF, PDGF-B No VHL or mutated VHL HIF accumulation Increased VEGF & PDGF Tumor cell growth, angiogenesis mTOR also overactive in RCC  incr HIF

Bajorian, D. Renal cell carcinoma

VHL Syndrome Von Hippel Lindau syndrome AD familial cancer syndrome
Mutation in 3p ccRCC, retinal angiomas, spinal & cerebellar hemangioblastomas, pheo, pancr CA, renal cysts 40% will have RCC. Retinal & CNS findings precede RCC leading cause of death in VHL syndrome Can also have sporadic defects in VHL gene Mutation Gene silencing via methylation

Birt-Hogg Dube Syndrome
Mutation in FLCN gene Chromosome 17 Kidney tumors (chromophobe common) Hair follicle tumors Spontaneous pneumothorax, lung cysts

Other hereditary syndromes
Hereditary Papillary RCC Papillary type 1 RCC C-Met mutations Bilateral, multifocal Hereditary Leiomyomatosis RCC Papillary type 2 RCC Uterine leiomyomas or leiomyosarcomas Germline mutation in fumarate hydratase Solitary aggressive tumors

Presentation + workup Painless hematuria, flank pain, +/- wt loss
Enhancing mass on CT – classic appearance of RCC Consider needle bx for small questionable mass CT c/a/p +/- brain MRI for staging Refer to Urology for resection FDG-PET not good for RCC G250 PET scan has high Se and Sp for ccRCC G a MAb binds to carbonic anhydrase IX (TM protein active in hypoxia, sustains tumor growth)

RCC intratumor heterogeneity
Gerlinger et al. NEJM 2012: Multi-region gene sequencing analysis on mulitple biopsy samples taken from two patients with met RCC Most mutations were not uniformly expressed at all tumor sites Some mutations were unique to a specific region Can express both favorable and unfavorable mutations in different regions of same tumor VHL found to be ubiquitous Can pose a challenge for tx response

Gerlinger et al. N Engl J Med 2012; 366:883-892

Stage I disease Small unilateral tumors (up to 7 cm, T1)
Curative surgery Long term complications of radical nephrectomy Partial nephrectomy (nephron-sparing surgery) Equally effective compared to radical nephrectomy in tumors < 7 cm Preferred over radical nephrectomy

Partial vs Radical nephrectomy
No statistically significant differences in cancer specific survival and distant metastases-free survival between patients treated with NSS and RN for RCC tumors 4-7 cm. Leibovich BC, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. J Urol Mar;171(3):

Stage I Non-surgical options: Usually for T1a small tumors
Active surveillance Ablative techniques (cryo, RFA) Usually for elderly, multiple co-morbidities Associated w/ increased risk of local recurrence

Stage II and III Radical nephrectomy
Preferred tx for tumors that extend to IVC Includes resection of perirenal fat, regional LN, and adrenalectomy Complete LN dissection is controversial Did not prolong OS in 1 prospective RCT

Predicting recurrence post-op
20-30% pts will relapse Most within 3 yrs Multiple nomograms, based on size, Furhman grade, TNM stage UCLA Integrated Staging System (UISS) MSKCC Moetzer Criteria Lam JS, et al. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol.2005 Aug;174(2):466-72; discussion 472; quiz 801.

Adjuvant? Almost 1/3 pts will relapse
Higher grade, T-stage  more likely to relapse Most common site of distant relapse  lungs Median time to relapse after surgery 1-2 yrs No FDA approved adjuvant tx after nephrectomy – for a long time… S-TRAC trial

Smaldone M, et al. Adjuvant and neoadjuvant therapies in high-risk renal cell carcinoma. Hematol Oncol Clin North Am.2011 Aug;25(4):

TKI adjuvant trials Pinto, A. Adjuvant Therapy for Renal Cell Carcinoma. Clin Genitourin Cancer.2014 Jun 21. pii: S (14) doi: /j.clgc [Epub ahead of print]

Risk status based on UCLA risk score
Risk status based on UCLA risk score. Higher risk = node positive, or node negative but high grade or T

ASSURE - DFS Arm 5-yr DFS Sunitinib 53.8% Sorafenib 52.8% Placebo
55.8% Haas, N et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Onc Volume 387, Issue 10032, 2016, 2008–2016

ASSURE - OS Arm 5-yr OS Sunitinib 76.9% Sorafenib 80.7% Placebo 78.7%
Haas, N et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Onc Volume 387, Issue 10032, 2016, 2008–2016

Conclusions from ASSURE
No survival benefit of sunitinib/sorafenib compared to placebo in this phase 3 RCT Toxicities of TKIs can lead to treatment discontinuation Could the biology of cancer recurrence be independent of angiogenesis?

S-TRAC Trial Oct 16, 2016  ravaud, Moetzer et al. NEJM
High risk – Stage III, positive LN N=615 randomized, double-blind, phase 3 trial, 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma assigned to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety.

Ravaud A et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1611406
S-TRAC DFS Arm mDFS Sunitinib 6.8 yrs Placebo 5.6 yrs HR 0.76 95% CI P = 0.03 Figure 2. Disease-free Survival. The median duration of disease-free survival according to independent central review was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group. At the time of data cutoff, an event of disease recurrence, a second cancer, or death had occurred in 113 of 309 patients (36.6%) in the sunitinib group and in 144 of 306 patients (47.1%) in the placebo group. Ravaud A et al. N Engl J Med DOI: /NEJMoa

S-TRAC trial Conclusions
OS data not mature at the time of data cutoff More grade 3-4 adverse events in sutent arm More dose reductions/interruptions in sutent For pts w/ locoregional ccRCC at high risk for recurrence s/p nephrectomy, adjuvant sutent x 1 yr led to a SS increase in mDFS

Adjuvant Sutent FDA approved for high risk ccRCC following nephrectomy
Approved 11/2017 based on S-TRAC data NCCN cat 2B 50 mg daily 4 weeks on/2 weeks off x 9 cycles (~1 year)

PROTECT trial pT2 or pT3 ccRCC s/p nephrectomy
Adj pazopanib vs placebo x 1 yr 10 endpoint DFS in 600 mg arm Starting dose of 800 mg following tx of ~400 pts was reduced to 600 mg to improve tolerability DFS for the ITT 600 arm was not significant 31% reduction in recurrence in ITT 800 arm Secondary endpoint

PROTECT Moetzer, et al. JCO Dec

Follow-up after nephrectomy
More aggressive f/u for higher risk H&P q3-6 mo x 2-3 yrs, then annually Baseline C/A/P scans within 3 mo s/p surgery Higher risk disease imaging every 6 mo for at least 3 years

Advanced Stage Mets Lung Bone Abdomen Liver Brain Adrenal

Stage IV Disease Prognostic models for advanced disease: Newer models:
MSKCC most widely used 5 variables: Interval dx to tx < 1 year KPS < 80% LDH> 1.5 x ULN Corrected Ca >ULN Hgb < LLN Newer models: IMDC criteria Thrombophilia Neutrophilia # Risk factors Risk Group Median OS (months) Favorable / low 29.6 1-2 Intermediate 13.8 >3 Poor 4.9 Mekhail TM, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol.2005 Feb 1;23(4):

Surgery for Stage IV Cytoreductive nephrectomy shown to be beneficial before systemic therapy in pts with (limited) metastatic disease Ideal patient: Primary RCC + solitary metastases Solitary recurrence after prolonged DFS s/p nephrectomy Good prognostic features Good PS

SWOG 8949 – NEJM 2001 Primary Endpoint: Cytoreductive Surgery Survival
Randomized Primary Endpoint: Survival Secondary Endpoint: Response to treatment Cytoreductive Surgery + IFN-a 246 mRCC pts: Eligible for nephrectomy Good PS No prior chemo No surgery + IFN-a Flanigan RC, et. al. Nephrectomy Followed by Interferon Alfa-2b Compared with Interferon Alfa-2b Alone for Metastatic Renal-Cell Cancer. NEJM :

Flanigan RC et al. N Engl J Med 2001;345:1655-1659.
SWOG Survival among All Eligible Patients, According to Treatment-Group Assignment. Arm Median Survival Surgery + IFN-a 11.1 mo IFN-a 8.1 mo p= 0.05 Figure 1. Actuarial Survival among All Eligible Patients, According to Treatment-Group Assignment. In the interferon-only group, there were 115 deaths and median survival was 8.1 months. In the surgery-plus-interferon group, there were 106 deaths and median survival was 11.1 months. Flanigan RC et al. N Engl J Med 2001;345:

SWOG EORTC 30947 Combined analysis of both trials showed median survival to favor surgery + IFN-a group 13.6 vs 7.8 mo for IFN-a alone Ongoing trials for surgery + TKI Keep in mind the ideal patient (low burden of mets, good PS) Can also consider surgical metastatectomy ‘neoadjuvant TKI’ under investigation

CARMENA trial

CARMENA Randomized phase III trial
450 pts w/ mRCC (intermediate / poor risk) CN followed by sunitinib Sunitinib alone 10 endpoint was OS Sunitinib alone is non-inferior to CN + sunitinib OS was surprisingly longer in sunitinib alone group (~18 mo) vs CN + sunitinib (~14 mo)

Other CN trials SURTIME Surgery upfront Sunitinib followed by surgery

Systemic treatment FDA 2015-2018: Nivolumab Cabozantinib
Lenvatinib + Everolimus Ipi +Nivo Adapted from Koletsky, A. Recent Advances in the treatment of renal cell carcinoma. New Orleans Summer Cancer Meeting, 2014.

Cytokine therapy Prior to 2005  HD IL-2 or IFN-a
Modest clinical benefit High toxicities Durable CR rate seen with HD IL-2

IL-2 Major responses in 10-15% pts with ccRCC
Durable responses in 4-5% pts Better in younger, good PS patients Higher dose more effective Substantial toxicity requires inpatient stay Increased vascular permeability often leading to hypotension, shock. 4% incidence of treatment-related death

Who gets IL-2? Younger age Good performance status
Few medical co-morbidities Not rapidly growing mets Presence of clear cell histology Proximity to an IL-2 specialty center Patient motivation Adapted from Koletsky, A. Recent Advances in the treatment of renal cell carcinoma. New Orleans Summer Cancer Meeting, 2014.

IFN-alpha 10-20% response rate No durable response
Higher response rate in small volume disease, primarily limited to lung IFN+IL-2 no better than IL-2 alone Maximal response with dose 5-20 mil units

Targeted Therapies

Choosing targeted therapy tumor histology and risk stratification
Currently approved First line: Sunitinib Pazopanib Bevacizumab + IFN-a Sorafenib Temsirolimus (poor risk) Axitinib New Ipi + Nivo New  cabozantinib Second Line Everolimus Nivolumab Cabozantinib Lenvatinib + Everolimus Any 1st line TKI choice Choosing targeted therapy tumor histology and risk stratification

Sunitinib Multikinase inhibitor: VEGF-1, 2, 3 receptor
PDGFR alpha, beta receptor C-kit FLT-3 RET Inhibits angiogenesis and proliferation

Sunitinib vs IFN-alpha

Sunitinib vs IFN-a for 1st line tx of met RCC
RANDOMIZED Sunitinib 50 mg po 4 wks on 2 wks off N=375 Eligibility Met ccRCC Untreated Most were favorable or intermed risk ECOG 0-1 N=750 N=375 IFN-alpha 9 M units SQ 3x/week Primary Endpoint: PFS Secondary Endpoint: RR, OS, Patient reported outcomes, safety

Motzer RJ et al. N Engl J Med 2007;356:115-124.
Kaplan–Meier Estimates of Progression-free Survival Arm mPFS Sunitinib 11 mo IFN-a 5 mo Arm RR Sunitinib 31% IFN-a 6% Figure 2. Kaplan–Meier Estimates of Progression-free Survival (Independent Central Review). No statistically significant difference in OS, but trend towards sunitinib 26.4 mo vs 21.8 mo , p=0.051 Motzer RJ et al. N Engl J Med 2007;356:

Adverse events Grade 3-4 in Sunitinib group: Grade 3-4 in IFN group:
Pancytopenia Diarrhea Hand-foot syndrome HTN (presence of HTN good response) Grade 3-4 in IFN group: Flu-like symptoms

Pazopanib Oral angiogenesis inhibitor targeting:
VEGF 1-3, PDGFR alpha & beta, c-kit.

Pazopanib vs placebo 435 pts w/met clear cell RCC
untreated OR 1 prior cytokine therapy Randomized to Pazopanib vs placebo 10= PFS 20= OS, RR, safety PFS (ss): 9.2 vs 4.2 mo RR: 30% vs 3 % No ss differences in OS Possibly related to cross over

Pazopanib vs placebo PFS
Treatment naïve group 11 vs 2.8 mo Pre-treated with cytokine 7.4 vs 4.2 mo

Pazopanib toxicities Diarrhea (52%) HTN (40%) Hair color changes (26%)
Nausea (26%) Grade 3 hepatotoxicity AST elevated (21%) ALT elevated (30%) Must monitor LFTs while on pazopanib

Pazopanib vs Sunitinib
COMPARZ trial (NEJM 8/2013) Non-inferiority study 1110 pts w/untreated mRCC randomized to P or S No ss differences in OS or PFS S more fatigue, hand-foot, thrombocytopenia, more alterations in taste P more LFT abnormalities Both have similar efficacy Results supported by smaller phase III PISCES trial Safety profile and quality of life domains favored Pazopanib

COMPARZ – PFS Pazopanib is non-inferior to Sunitinib in terms of PFS OS was similar Figure 1. Kaplan–Meier Estimates of Progression-free Survival According to Independent Review. The median progression-free survival was 8.4 months with pazopanib (95% CI, 8.3 to 10.9) and 9.5 months with sunitinib (95% CI, 8.3 to 11.1). The dotted line represents the median (0.5), and vertical lines represent 95% confidence intervals. Motzer RJ et al. N Engl J Med 2013;369:

Pazopanib favored Adapted from Koletsky, A. Recent Advances in the treatment of renal cell carcinoma. New Orleans Summer Cancer Meeting, 2014.

Bevacizumab + IFN alpha
AVOREN trial (Lancet 12/2007) 649 pts randomized Bev+ IFN vs placebo + IFN PFS: 10.2 vs 5.4 mo Response Rate 30.6% vs 12.4% No statistically significant differences in OS 23.3 vs 21.3 mo More fatigue and asthenia in Bev group AE: HTN, proteinuria

AVOREN – OS, PFS PFS: 10.2 vs 5.4 mo; HR 0.63; p<0.001
No ss diff in OS Escudier B, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. The Lancet. Dec 2007 Volume 370, Issue 9605, 2008, 2103–2111

Anti-VEGF TKI toxicities
Sunitinib / pazopanib / sorafenib / axitinib Fatigue HTN Diarrhea Hand-foot syndrome Thrombocytopenia Hypothyroidism CHF Hepatotoxicity Pazopanib Hair color changes Pazopanib SBP > 140 assoc w/better response to sunitinib ‘-ib’  CYP3A4, watch for drug-drug interactions

Temsirolimus mTOR regulates micronutrients, cell growth, angiogenesis
frequently activated in RCC Temsirolimus is mTOR inhibitor ARCC trial (NEJM – May 2007) 626 previously untreated mRCC pts w/ >3 poor prognostic factors: LDH, hgb, Ca, PS, timing <1 yr, #metastases Randomized to Temsirolimus 25 mg IV weekly IFN-a (3 MU TIW) Both (Tem 15 mg IV weekly + 6 MU IFN TIW) Primary endpoint = OS

Hudes G et al. N Engl J Med 2007;356:2271-2281.
ARCC - OS (Panel A) and PFS (Panel B). Pts who received temsirolimus alone had longer OS (HR for death, 0.73; p=0.008) and PFS (p<0.001) than did patients who received interferon alone Arm mOS Tem 10.9 mo IFN-a 7.3 mo Both 8.4 mo Figure 1. Kaplan–Meier Estimates of Overall Survival (Panel A) and Progression-free Survival (Panel B). Combo arm = no better than Tem alone. Did not increase survival and was more toxic Hudes G et al. N Engl J Med 2007;356:

ARCC – adverse events More common in Tem arm: Rash Peripheral edema
Hyperglycemia Hyperlipidemia Asthenia was more common w/ IFN More grade 3-4 in combo group Tem FDA approved for 1st line poor risk

CheckMate 214 – Ipi/Nivo vs Sunitinib in mRCC
1096 pts intermediate to poor risk Ipilimumab (1mg/kg) + nivolumab (3 mg/kg) q3 weeks x 4 cycles  nivo maintenance q2 wks sunitinib 50 mg - 4 wks on/2 wks off 10 endpoint – OS, oRR, PFS 18 mo OS 75% Ipi/Nivo vs 60% S oRR 42% Ipi/Nivo vs 27% S Some CR in Ipi/Nivo arm Similar rates of adverse events, but more discontinuations in Ipi/Nivo group

RJ Motzer et al. N Engl J Med 2018;378:1277-1290.
Overall Survival and Progression-free Survival among IMDC Intermediate- and Poor-Risk Patients. Ipi/Nivo now a category 1 rec on NCCN for 1st line treatment of mRCC Figure 1. Overall Survival and Progression-free Survival among IMDC Intermediate- and Poor-Risk Patients. Progression was defined according to the Response Evaluation Criteria in Solid Tumors, version 1.1. For progression-free survival, the between-group difference did not meet the prespecified threshold (P=0.009) for statistical significance. IMDC denotes International Metastatic Renal Cell Carcinoma Database Consortium, NE not estimable, and NR not reached. RJ Motzer et al. N Engl J Med 2018;378:

CABO-SUN trial Cabozantinib vs sunitinib as 1st line tx met RCC
157 intermediate or poor risk pts randomized to either cab 60 qd or sutent 50 qd (4 on/2 off) Primary endpoint PFS Other endpoints  oRR, OS, safety mPFS  8.2 vs 5.6 mo oRR 33% vs 12% Similar adverse events in both arms Diarrhea, fatigue, HTN, PPE Cabozantinib 1st line FDA approved 12/2017 Intermediate-poor risk mRCC

Second line / subsequent therapies

Current FDA approved First line: Second Line Ipi/Nivo Sunitinib
Pazopanib Bevacizumab + IFN-a Sorafenib (poor data for 1st line) Temsirolimus Axitinib (traditionally 2nd line) Second Line Everolimus Nivolumab Cabozantinib Lenvatinib + Everolimus Any 1st line TKI choice

Sorafenib Inhibits VEGF, PDGFR, c-kit,FLT-3, RET
Phase III study (TARGET, NEJM 2007) showed efficacy for 2nd line (after cytokine failure) Phase II study for 1st line Untreated pts randomized to sorafenib vs IFN No SS difference in PFS mPFS 5.7 vs 5.6 mo (HR=0.88, p=0.504) Nccn category 2a for 1st line and second line

Side effects: grade 3-4 hand foot, fatigue, HTN
SS diff in PFS led to large crossover, therefore no initial diff in OS. However, with censoring of crossover data, there was a significant diff in OS: 17.8 vs 14.3 months (HR=0.78; p=0.0287) Side effects: grade 3-4 hand foot, fatigue, HTN Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Axitinib 2nd gen VEGFR 1,2 inhibitor
2nd line tx - AXIS trial (Lancet, 2011) 723 pts who failed 1 prior tx (cytokine or sunitinib) Randomized to Axitinib 5 mg BID Sorafenib 400 mg BID PFS 6.7 vs 4.7 mo (HR= 0.66, p<0.0001) PFS favored Axitinib in both pre-treated groups No signif difference in OS HTN, fatigue, dysphonia = more in Axitinib Hand-foot, rash, alopecia, anemia = more in Sorafenib

Axitinib as first line Phase III trial in Lancet Oncol 2013
Newly diagnosed, untreated Axitinib vs Sorafenib mPFS 10.1 mo vs 6.5 mo not statistically significant Clinical activity as 1st line with acceptable toxicity Phase II trial in Lancet Oncol 2013 on dose titration of Axitinib (5, 7, 10 mg bid) Higher RR in dose-titrated group Category 2a rec on NCCN for 1st line mRCC

Everolimus Oral mTOR inhibitor
2nd line tx - RECORD 1 trial (Lancet, 2008) Phase III double blind RCT 410 pts who failed TKI  sunitinib or sorafenib Randomized everolimus vs placebo 10 endpoint  PFS

RECORD-1 PFS Arm mPFS Everolimus 4 mo Placebo 1.9 mo
HR=0.3; p<0.0001 Probability for being progression-free at 6 mo 26% vs 2% Side effects: Stomatitis Rash Fatigue Pneumonitis Moetzer, et al. Lancet 2008

Cabozantinib Targets VEGF, MET, AXL
FDA approved for medullary thyroid CA Phase I studies for heavily pre-treated mRCC Phase III METEOR trial (Chouri, et al. NEJM 2015) Exelixis.com

Choueiri TK et al. N Engl J Med 2015;373:1814-1823.
METEOR - PFS Arm mPFS Cabozantinib 7.4 mo Everolimus 3.8 mo Final analysis showed SS increase in OS for Cabo arm. mOS 21.4 vs 16.5 mo (HR=0.66, p= ) More dose reductions in Cabo arm due to side effects: Diarrhea, hand-foot, fatigue Figure 2. Kaplan–Meier Estimates of Progression-free Survival. Disease progression was assessed by an independent radiology review committee. Choueiri TK et al. N Engl J Med 2015;373:

Lenvatinib + Everolimus
Lenvatinib –multikinase agent targeting VEGF, PDGF-α, RET, KIT receptors, and FGF receptor Approved for RAI-refractory thyroid CA Phase II small study, Moetzer et al Lancet 11/2015 Lenvatinib vs Everolimus vs Both PFS favored Len+Ev arm vs Ev alone More side effects with combo arm diarrhea

Lenvatinib ± Everolimus in mRCC: Randomized, Open-Label Phase II Study
Stratified by hemoglobin (low vs normal) and corrected serum calcium (≥ vs < 10 mg/dL) Lenvatinib 18 mg QD + Everolimus 5 mg QD (n = 51) Measurable metastatic or advanced RCC; following progression ≤ 9 mos after 1 prior VEGF therapy (N = 153) Lenvatinib 24 mg QD (n = 52) Treated until PD or unacceptable toxicity Everolimus 10 mg QD (n = 50) mRCC, metastatic renal cell carcinoma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; QD, once daily; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor. David F. McDermott, MD: Motzer and colleagues[1] presented the results of a randomized phase II trial investigating lenvatinib, a novel tyrosine kinase inhibitor, in 153 patients with advanced or metastatic RCC following progression after 1 previous vascular endothelial growth factor (VEGF) therapy. Patients were randomized to either lenvatinib, everolimus, or a combination of both agents. Lenvatinib is an agent that targets the VEGF, PDGF-α, RET, KIT receptors, and most important, the FGF receptor. It is well known that targeting the VEGF pathway, either by binding the protein in circulation with antibodies such as bevacizumab or blocking the receptor with tyrosine kinase inhibitors (TKIs) such as sunitinib, can lead to improvements in progression‑free survival (PFS) and, when administered sequentially, OS; our patients are clearly living longer with these agents. However, resistance to VEGF blockade is inevitable. There have been many preclinical experiments performed in an attempt to understand the pathways that drive this resistance. The FGF signaling pathway has been proposed as an important escape mechanism that tumors use to restore oncogenesis when the VEGF receptor is inhibited. Lenvatinib is a novel agent that blocks a receptor believed to be important in driving resistance to standard therapies. One interesting aspect of this study design is that in previous trials, we have not been able to combine standard therapies very well. Although we have struggled with toxicity and dose reductions of the standard agents to allow patients to tolerate the combinations, given the inevitability of resistance, combination therapies seem rational to explore. Of note, in the combination arm of lenvatinib and everolimus, the doses of both agents had to be reduced to safely administer them together. The primary endpoint was PFS of patients who received lenvatinib with or without everolimus vs everolimus alone. Secondary endpoints included PFS of the combination vs lenvatinib alone, overall response rate (ORR), OS, and safety. Reference: 1. Motzer R, Hutson T, Glen H, et al. Randomized phase II, three-arm trial of lenvatinib (LEN), everolimus (EVE), and LEN+EVE in patients (pts) with metastatic renal cell carcinoma (mRCC). Program and abstracts from the 2015 American Society of Clinical Oncology Annual Meeting; May 29 - June 2, 2015; Chicago Illinois. Abstract 4506. Primary endpoint: PFS with lenvatinib ± everolimus vs everolimus alone Secondary endpoints: PFS with combination vs lenvatinib alone, ORR, OS, safety/tolerability Motzer R, et al. ASCO Abstract Reprinted with permission.

Lenvatinib ± Everolimus in mRCC: Efficacy
Response Lenvatinib/ Everolimus (n = 51) Lenvatinib (n = 52) Everolimus (n = 50) Median PFS, mos 14.6 HR: 0.40; P < .001 vs everolimus 7.4 HR: 0.61; P = .048 5.5 ORR, % 43 P < .001 vs everolimus 27 P = .007 vs everolimus 6 Median OS,* mos 25.5 HR: 0.51; P = .024 19.1 HR: 0.68; P =.118 15.4 mRCC, metastatic renal cell carcinoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. David F. McDermott, MD: Several interesting observations were made from this study. Patients in the lenvatinib-alone cohort showed numerically greater PFS, ORR, and OS than patients in the everolimus alone group, with ORR reaching statistical significance and PFS nearly reaching statistical significance. Patients who received the combination of lenvatinib plus everolimus had a significantly greater PFS vs patients in the lenvatinib-only and everolimus-only cohorts (14.6, 7.4, and 5.5 months, respectively; P < .001 for combination vs everolimus), and a significantly higher ORR of 43% vs 27% and 6%, respectively (P < .001 for combination vs everolimus), as well as a statistically significant improvement in median OS of 25.5 months vs 19.1 months and 15.4 months, respectively (P = .024 combination vs everolimus). *Updated analysis. Motzer R, et al. ASCO Abstract Reprinted with permission.

Nivolumab Blocks PD-1 and PDL-1 interactions, unleashing immune response Approved for lung, melanoma, renal, Hodgkins, head & neck Checkmate 025 phase III RCT

CheckMate 025: Phase III Study Design
Treated beyond progression (n = 153) Treated briefly beyond progression (n = 18) Not treated beyond progression (n = 145) Progressed (n = 316) Did not progress (n = 90) (n = 320) (n = 77) Pts with advanced ccRCC, KPS ≥ 70%, 1-2 previous antiangiogenic agents, progression ≤ 6 mos before enrollment (N = 803) Nivolumab 3 mg/kg IV Q2W (n = 406) Everolimus 10 mg PO QD (n = 397) Treated beyond progression (n = 65) Treated briefly beyond progression (n = 111) Not treated beyond progression (n = 144) KPS, Karnofsky performance status; RCC, renal cell carcinoma. Primary endpoint: OS Secondary endpoints: ORR, safety Subgroup analyses: efficacy, safety from baseline to first progression, at and after first progression Slide credit: clinicaloptions.com Escudier BJ, et al. ASCO Abstract 4509.

Checkmate OS Arm mOS Nivolumab 25 mo Everolimus 19.6 mo Nivolumab appeared to increase OS in patients treated beyond progression as well (ASCO GU 2016) More grade 3-4 adverse events in everolimus group Figure 1. Kaplan–Meier Curve for Overall Survival. CI denotes confidence interval, and NE not estimable. Motzer RJ et al. N Engl J Med 2015;373:

Sequencing treatment

Optimal sequencing Pazopanib / Sunitinib / Ipi+Nivo1st line
Nivolumab/Cabozantinib 2nd line Everolimus or other TKI  3rd line Depends on side effects, tolerability, duration of response Concurrent use of 2 targeted agents may improve RR but w/ increased toxicities Combination studies failed to show benefits in PFS, whereas sequential use dose improve PFS and OS

Non-clear cell RCC Less studied, most trials were on clear cell
Clinical trial favored Start with TKI Sunitinib & Sorafenib  phase II trials Temsirolimus ARCC trial included subset of non-clear cell pts Everolimus phase II trials Erlotinib Small study in papillary RCC pts 11% partial response rate

Chemotherapy in RCC RCC resistant to chemo except sarcomatoid, medullary or collecting duct CA RCC with sarcomatoid features: Gemcitabine + Adriamycin Phase II study: ORR 16%, mPFS 3.5 mo, mOS 8.8 mo Gemcitabine + Capecitabine Medullary CA & Collecting Duct CA Gemcitabine + Cis or Carboplatin ORR 26%, OS 10.5 mo

Supportive Care Bone mets occur in 30-40% pts w/advanced RCC
Radiation to bony mets Zometa or Denosumab delays time to SRE Stereotactic XRT vs surgery vs whole brain XRT for brain mets Pts with treated brain mets may safely receive tx with multikinase inhibitors

New studies in RCC Other immune checkpoint inhibitors:
Pembrolizumab +/- TKI Atezolizumab +/- TKI Avelumab Ixazomib - proteosome inhibitor Crizotinib - ALK inhibitor Tivantinib - MET inhibitor Dovitinib – multikinase inhibitor Foretinib - MET/VEGF inhibitor for papillary RCC

PROSPER - RCC Phase III RCT
Perioperative Nivolumab vs observation in patients with localized RCC undergoing nephrectomy Pre-op Nivo Surgery Post-op Nivo Surgery Observation

Case 66 yo male p/w L flank pain and hematuria x 1 mo. CT scan shows 7.8 cm L renal enhancing mass, suspicious for RCC. No other distant mets or LNs. Of note, his PMHx includes Stage II ccRCC in R kidney diagnosed in 2007 s/p radical nephrectomy. Had no e/o recurrence for past 7 years until now. He is refusing dialysis.

Neoadjuvant therapy with TKI
12 patients were given TKI (sunitinib) before NSS Mean pretreatment tumor diameter was 7.1 cm All tumors shrunk after TKI. Mean reduction in max diameter of 1.5 cm NSS was achievable in all. Postoperative dialysis was not required in any patients. Final pathology revealed negative tumor margins in all Need more randomized data

Summary RCC is a heterogeneous disease
Angiogenesis is a key molecular target VEGF mTOR NSS preferred over radial nephrectomy Cytoreductive nephrectomy may be beneficial in stage IV IL-2 - durable response TKIs increase PFS Sunitinib or Pazopanib or Ipi/nivo 1st line Nivolumab or cabozantinib 2nd line (both are better than everolimus) Limited data on non-clear cell histologies Chemo doesn’t work

R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018

Similar presentations

Presentation on theme: "R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018

Similar presentations

Presentation on theme: "R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018"— Presentation transcript:

Similar presentations

About project

Feedback